Probing the reactivity of α,β-unsaturated acyl ammonium intermediates in organocatalysis

Abstract

The research described in this thesis focuses on probing the reactivity of α,β-unsaturated acyl ammonium intermediates and the use of theses reactive intermediates in a new concept: aryloxide-facilitated catalyst turnover in α,β-unsaturated acyl ammonium catalysis.

Chapter 2: Initially, the concept of aryloxide-facilitated catalyst turnover was used in a novel isothiourea-catalysed transfer hydrogenation reaction of α,β-unsaturated p-nitrophenyl esters. An efficient synthetic procedure was successfully developed, which was demonstrated to be applicable to a range of α,β-unsaturated PNP esters (15 examples, 38−98% yield), typically with electron withdrawing β-substituents proving most reactive. Attempts to perform the reaction enantioselectively showed that in principle α,β-unsaturated acyl ammonium intermediates generated from α,β-unsaturated PNP esters and a chiral isothiourea catalyst can react enantioselectively.

Chapter 3: Following on the established new concept in α,β-unsaturated acyl ammonium catalysis, enantioselective Michael addition of nucleophiles to α,β-unsaturated PNP esters has been further explored using the aryloxide-facilitated catalyst turnover strategy. This new method was applicable for a range of malonates and malonate derivatives as pro-nucleophiles, resulting in generally good yields with excellent enantioselectivities (14 examples, up to 86% yield, > 99:1 er). This work demonstrated for the first time that simple nucleophiles could be applied in stoichiometric quantities in enantioselective a,b-unsaturated acyl ammonium catalysis.

Chapter 4: A detailed variable time normalisation kinetic analysis (VTNKA) was performed to investigate the kinetics of the enantioselective Michael addition of malonates to α,β-unsaturated PNP esters, using 19F{1H} NMR spectroscopic analysis. The order with respect to α,β-unsaturated ester, malonate and catalyst were found to be first order, but zero order with respect to base, indicating the turnover-limiting step is likely to be the Michael addition of malonate to the α,β-unsaturated acyl ammonium intermediate.